In unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve replacement, reocclusion after angioplasty, thrombus formation during extracorporeal circulation and the like, enhancement of blood coagulability is one of crucial factors. Therefore, there is a demand for excellent anticoagulants which have excellent dose responsiveness, sustainability, reduced risk of hemorrhage and few side effects, and can immediately exhibit satisfactory effects even when orally administered (Non-Patent Document 1).
Among various studies of anticoagulants based on mechanisms of action, it is suggested that FXa inhibitors have a potential to be excellent anticoagulants. The blood coagulation system comprises a series of reactions in which a large amount of thrombin is produced through an amplification process with a multi-stage enzymatic reaction to form insoluble fibrin. In an endogenous system, after a multi-stage reaction following the activation of a contact factor, activated factor IX activates factor X on a phospholipid membrane in the presence of activated factor VIII and calcium ions. In an exogenous system, activated factor VII activates factor X in the presence of a tissue factor. In other words, activation of the factor X into FXa in the coagulation system is an essential reaction for the formation of thrombin. In both systems, the activated factor X (FXa) limitedly degrades prothrombin to produce thrombin. Since the produced thrombin activates the upstream coagulation factors, the generation of thrombin is further amplified. As described above, since the coagulation system upstream of FXa is divided into an endogenous system and an exogenous system, inhibiting the enzymes in the coagulation system upstream of FXa cannot sufficiently suppress production of FXa, and accordingly, thrombin is produced. Meanwhile, since the coagulation system involves self-amplification reactions, suppression of the coagulation system can be efficiently achieved by inhibiting FXa, which is upstream of thrombin, rather than by inhibiting the already produced thrombin (Non-Patent Document 2). Another excellent advantage of FXa inhibitors is that there is a large difference between the dose which is effective in a thrombosis model and the dose which prolongs bleeding time in an experimental hemorrhage model. From these experimental results, it is conceived that FXa inhibitors are anticoagulants with reduced risk of hemorrhage.
Various compounds have been reported as FXa inhibitors. However, it is known that antithrombin III and antithrombin III-dependent pentasaccharides generally cannot inhibit prothrombinase complexes which play a practical role in the thrombus formation in vivo (Non-Patent Documents 3 to 5), and furthermore, they do not exhibit effectiveness when orally administered. Tick anticoagulant peptide (TAP) (Non-Patent Document 3) and antistasin (AST) (Non-Patent Document 4), which are isolated from bloodsucking animals such as mites or leeches, also inhibit FXa and exhibit anti-thrombotic effects in venous thrombosis models as well as arterial thrombosis models. However, these compounds are high molecular weight peptides, and ineffective when orally administered. As such, low-molecular weight FXa inhibitors have been developed, which can be orally administrable and directly inhibit coagulation factors without depending antithrombin III.    [Non-Patent Document 1] Thrombosis Research, Vol. 68, pp. 507-512 (1992)    [Non-Patent Document 2] Thrombosis Research, Vol. 15, pp. 617-629 (1979)    [Non-Patent Document 3] Science, Vol. 248, pp. 593-596 (1990)    [Non-Patent Document 4] Journal of Biological Chemistry, Vol. 263, pp. 10162-10167 (1988)